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<p>Epigenome-wide studies of pancreatic islets provide valuable insights into type 2 diabetes (T2D) but lack methylomes from individual cell types. Here we show changes to alpha and beta cell-specific methylomes and transcriptomes from people with or without T2D, using whole-genome bisulfite sequencing and RNA sequencing. We discover 22,544 differentially methylated regions annotated to 7,975 genes in alpha versus beta cells, such as <i>INS</i>, <i>GCG</i>, <i>PDX1</i> and <i>PCSK1</i>, with ~50% showing differential expression. CRISPR–dCas9–DNMT3A-based epigenetic editing increases <i>INS</i> and <i>TH</i> DNA methylation, while CRISPR–dCas9–TET1-based editing decreases <i>GCG</i> methylation, each altering <i>INS, TH</i> or GCG expression and content in beta cells. Pre-T2D/T2D-associated differentially methylated regions in alpha and beta cells overlap 12–18% of T2D-associated genome-wide association study candidates. Additionally, <i>ONECUT2</i> is epigenetically upregulated in beta cells from people with pre-T2D/T2D and elevated in male Goto-Kakizaki rat islets. ONECUT2 overexpression in beta cells/islets downregulates gene sets impacting insulin secretion and glucose homeostasis, and reduces mitochondrial activity, ATP/ADP ratio and insulin secretion. We also provide ‘alpha-beta-methylome’ (<a href="https://alpha-beta-methylome.serve.scilifelab.se/app/alpha-beta-methylome/">https://alpha-beta-methylome.serve.scilifelab.se/app/alpha-beta-methylome/</a>), a resource exploring T2D, age and sex associations on methylation, highlighting cell-specific epigenetic regulation and dysfunctions contributing to T2D.</p>

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Cell-specific DNA methylation in human alpha and beta cells regulates gene expression in type 2 diabetes

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月24日

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  • Jones K. Ofori,
  • Sabrina Ruhrmann,
  • Axel Lindström,
  • Alexander Perfilyev,
  • Melina Martin,
  • Alexandros Karagiannopoulos,
  • Lucia Scisciola,
  • Katja Kost,
  • Josefine Jönsson,
  • Åsa Nilsson,
  • Boris Kantor,
  • Monika Dudenhöffer-Pfeifer,
  • Marianne G. Rots,
  • Anna Wendt,
  • Tina Rönn,
  • Lena Eliasson,
  • Karl Bacos,
  • Charlotte Ling

摘要

Epigenome-wide studies of pancreatic islets provide valuable insights into type 2 diabetes (T2D) but lack methylomes from individual cell types. Here we show changes to alpha and beta cell-specific methylomes and transcriptomes from people with or without T2D, using whole-genome bisulfite sequencing and RNA sequencing. We discover 22,544 differentially methylated regions annotated to 7,975 genes in alpha versus beta cells, such as INS, GCG, PDX1 and PCSK1, with ~50% showing differential expression. CRISPR–dCas9–DNMT3A-based epigenetic editing increases INS and TH DNA methylation, while CRISPR–dCas9–TET1-based editing decreases GCG methylation, each altering INS, TH or GCG expression and content in beta cells. Pre-T2D/T2D-associated differentially methylated regions in alpha and beta cells overlap 12–18% of T2D-associated genome-wide association study candidates. Additionally, ONECUT2 is epigenetically upregulated in beta cells from people with pre-T2D/T2D and elevated in male Goto-Kakizaki rat islets. ONECUT2 overexpression in beta cells/islets downregulates gene sets impacting insulin secretion and glucose homeostasis, and reduces mitochondrial activity, ATP/ADP ratio and insulin secretion. We also provide ‘alpha-beta-methylome’ (https://alpha-beta-methylome.serve.scilifelab.se/app/alpha-beta-methylome/), a resource exploring T2D, age and sex associations on methylation, highlighting cell-specific epigenetic regulation and dysfunctions contributing to T2D.